Abstract
The progression of diabetic complications does not halt despite termination of hyperglycemia,
suggesting a “metabolic memory” phenomenon. However, whether metabolic memory exists
in and affects the healing of diabetic wounds, as well as the underlying molecular
mechanisms, remain unclear. In this study, we found that wound healing was delayed
and angiogenesis was decreased in diabetic mice, despite normalization of glycemic
control. Thus, we hypothesized that transient hyperglycemic spikes may be a risk factor
for diabetic wound healing. We showed that transient hyperglycemia caused persistent
damage to the vascular endothelium. Transient hyperglycemia directly upregulated DNMT1
expression, leading to the hypermethylation of Ang-1 and reduced Ang-1 expression,
which, in turn, induced long-lasting activation of nuclear factor (NF)-κB and subsequent
endothelial dysfunction. An in vivo study further showed that inhibition of DNMT1
promoted angiogenesis and accelerated diabetic wound healing by regulating the Ang-1/NF-κB
signaling pathway. These results highlight the dramatic and long-lasting effects of
transient hyperglycemic spikes on wound healing and suggest that DNMT1 is a novel
target for diabetic vascular complications.
Key words
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Article Info
Publication History
Accepted:
October 26,
2020
Received in revised form:
October 11,
2020
Received:
May 21,
2020
Publication stage
In Press Journal Pre-ProofFootnotes
This work was done in Guangzhou, Guangdong, China.
Conflicts of Interest: The authors declare that they have no competing interests.
Identification
Copyright
© 2020 The Authors. Published by Elsevier, Inc. on behalf of the Society for Investigative Dermatology.
